This invention generally pertains to heterocyclic carbon compounds having drug and bio-affecting properties and to their preparation and use. In particular, the invention is concerned with a series of new 2,3-dihydro-2-oxo-1H-imidazo[4,5-b]quinolinyloxyalkanoic acid amides wherein a basic nitrogen atom is incorporated in the amide grouping. The alkanoic amide derivatives are phosphodiesterase inhibitors, blood platelet antiaggregators and cardiotonic agents.
The heterocycle "2,3-dihydro-2-oxo-1H-imidazo[4,5-b]quinoline" of formula (1), alternately referred to as 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one, was described by Kozak, et al., Bull. Intern. Acad. Polanaise, 1930A, 432-438 (Chem. Abs. 25, 5400) ##STR2##
Derivatives of formula (1) having cyclic AMP phosphodiesterase inhibitory activity have been prepared and studied for their platelet inhibition and cardiotonic properties. Thus, for example:
Meanwell, et al., U.S. Pat. No. 4,775,674 describe a series of 2,3-dihydro-2-oxo-1H-imidazo[4,5-b]quinolinyl ether derivatives of formula (2) ##STR3## wherein R.sub.1 is hydrogen, lower alkyl, benzyl R.sub.2 is hydrogen, halogen, lower alkyl lower alkoxy; Alk is alkylene; Y is hydroxy and alkanoic or aralkanoic esters thereof, oxo ketone, dialkylamino, carboxylic acid and esters, carboxamides, alkoxy, ethanolamines and cyclic carbamates thereof, tetrazolyl, and optionally substituted phenylsulfonyl.
Meanwell et al., U.S. Pat. No. 4,701,459 describe another series of 2,3-dihydro-2-oxo-1H-imidazo-[4,5-b]quinoline compounds comprising amine derivatives of formula (3) ##STR4## wherein R.sub.1 is hydrogen, lower alkyl; R.sub.2 is hydrogen, lower alkyl, lower alkoxy, halogen; R.sub.3 is hydrogen, lower alkyl; R.sub.4 is hydrogen, lower alkyl, alkanoyl, phenylalkanoyl wherein phenyl is optionally substituted with halogen, lower alkyl, lower alkoxy, R.sub.3 and R.sub.4 are joined together to form morpholinyl, piperidinyl or pyrrolidinyl optionally substituted with --CO.sub.2 R.sub.5 or ##STR5## wherein R.sub.5 is hydrogen or lower alkyl, and R.sub.6 is hydrogen, lower alkyl, cycloalkyl; 4-R.sub.7 -piperazinyl wherein R.sub.7 is --CO.sub.2 R.sub.8 wherein R.sub.8 is lower alkyl, phenyl optionally substituted with up to 2 halogen, lower alkyl or lower alkoxy: phenylalkanoyl of 7 to 10 carbon wherein phenyl is unsubstituted or independently substituted with up to 2 halogen, lower alkyl, lower alkoxy.
Meanwell, et al., U.S. Pat. No. 4,668,686 describe still another series of 1,3-dihydro-2H-imidazo-[4,5-b]quinolin-2-ones comprising derivatives of formula (4) ##STR6## wherein R.sub.1 is halogen, lower alkyl, lower alkoxy, trifluoromethyl; R.sub.2 is hydrogen, halogen, lower alkyl, lower alkoxy; R.sub.3 is hydrogen, halogen, lower alkyl, lower alkoxy; and R.sub.4 is hydrogen or lower alkyl.
Another class of heterocyclic compounds having phosphodiesterase inhibiting and anti-platelet aggregation activity comprise the tetrahydroimidazo[2,1-b]quinazolin-2-ones of formula (5). ##STR7##
For example:
Beverung, Jr., et al., U.S. Pat. No. 3,932,407 disclose a series of compounds useful as blood platelet antiaggregative and/or antihypertensive and/or bronchodilator agents of the tetrahydroimidazo[2,1-b]- quinazolin-2-one class. Anagrelide (6), a particularly preferred member of the Beverung, Jr., et al. series, has been studied extensively, e.g., J. S. Fleming, et al., New Drugs Annual: Cardiovascular Drugs, Raven Press, pages 277-294, New York (1983). ##STR8##
Chodnekar, et al., U.S. Pat. No. 4,256,748 describe a series of tetrahydroimidazo[2,1-b]quinazolin-2-ones of the formula (7) as inhibitors of the aggregation of blood platelets and cardiotonic activity. ##STR9## Representative of the Chodneker compounds are RO 15-2041 (R.sup.4 .dbd.CH.sub.3, R.sup.3 .dbd.H, R.sup.2 .dbd.6-CH.sub.3, R.sup.1 .dbd.7-Br) and RO 13-6438 (R.sup.4 .dbd.CH.sub.3, R.sup.3 .dbd.H, R.sup.2 .dbd.6-CH.sub.3, R.sup.1 .dbd.H).
Jones, et al., U.S. 4,490,371 describe another series of tetrahydroimidazo[2,1-b]quinazolin-2-one derivatives as cyclic AMP phosphodiesterase inhibitors useful as thrombogenic agents. Among the compounds disclosed is the formula (8) amide, identified in the art as RS82856. ##STR10##
Jones, et al., European Patent Application 153152 further describe tetrahydroimidazo[2,1-b]quinazolin-2-ones of formula (9) as cyclic AMP phosphodiesterase inhibitors useful as antithrombogenic agents. ##STR11##
Compounds of the aforementioned patents generally display limited solubility in water, acidic or alkali media and common organic solvents. For instance, the formula (2) compound "1-[4-[(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]- quinolin-7-yl)oxy]-1-oxobutyl]-4-phenylpiperazine" has a solubility of less than 0.01 milligrams per milliliter of water or 2.0N HCl.